The present invention relates to a process for producing piperonal, more specifically to a process for producing a high quality piperonal with high yield by using 1,2-methylenedioxybenzene as a starting material and without taking 3,4-methylenedioxymandelic acid which is an intermediate in the course of the reaction as a crystal.
Piperonal is a base material for preparing a heliotrope type perfume and has widely been used as a perfume for general cosmetics, and in addition, it is a useful compound as a starting material for synthesis of medical and agricultural chemicals and a brightener for metal plating.
As a method for producing piperonal, it has been generally known a method of oxidizing 3,4-methylenedioxy-mandelic acid with nitric acid (for example, P. S. Raman Current Science, 27, 22 (1958), Perfumer and Flavourist, 14, 13 (1989), EP 429316, etc.). Also, it has been known that 3,4-methylenedioxymandelic acid can be produced by reacting 1,2-methylenedioxybenzene and glyoxylic acid in the presence of sulfuric acid, etc. (for example, Japanese Provisional Patent Publication No. 95573/1979, Perfumer and Flavourist, 14, 13 (1989), etc.).
In the method of producing piperonal through 3,4-methylenedioxymandelic acid as mentioned above, the 3,4-methylenedioxymandelic acid formed by the initial reaction (hereinafter referred to as addition reaction) of 1,2-methylenedioxybenzene and glyoxylic acid is insoluble in the reaction system and precipitates as crystals. Thus, after separating the crystals of the 3,4-methylenedioxy-mandelic acid by an operation such as filtration, a subsequent reaction (hereinafter referred to as oxidation reaction) of 3,4-methylenedioxymandelic acid and nitric acid has been carried out. However, operations such as filtration, etc. are complicated, and this method is disadvantageous as an industrial preparation process.
On the other hand, it has been known a process for producing piperonal by carrying out an addition reaction and an oxidation reaction continuously without separating and purifying 3,4-methylenedioxymandelic acid in the course of the operations (Japanese Provisional Patent Publication No. 330755/1995). In this process, a relatively high quality piperonal can be produced with high yield. However, at the time of oxidation reaction, 1,2-methylene-dioxy-4-nitrobenzene is contaminated in crude piperonal in an amount of 0.5 to 1.0% by weight or so. This 1,2-methyl-enedioxy-4-nitrobenzene is a compound which can be confirmed to be colored with naked eyes even when it is contaminated in piperonal in an amount of several tens ppm or more, and when it is once formed, it is difficult to remove from piperonal by a general purification method such as distillation, recrystallization, activated charcoal treatment, etc. Thus, there is a problem of lowering quality of the product by causing coloring of piperonal.
An object of the present invention is to provide a process which is capable of producing a high quality piperonal with high yield by completely inhibiting formation of 1,2-methylenedioxy-4-nitrobenzene, without taking out 3,4-methylenedioxymandelic acid which is an intermediate in the course of the reaction as a crystal, and carrying out from the above-mentioned addition reaction step to the oxidation reaction step continuously using 1,2-methylenedioxybenzene as a starting material.
The present invention relates to a process for producing piperonal which comprises three steps of:
(A) an addition reaction step wherein 1,2-methylenedioxy-benzene and glyoxylic acid are reacted to form 3,4-methyl-enedioxymandelic acid in the presence of a strong acid,
(B) an extraction step wherein thereafter, an organic solvent is then added to a reaction mixture and the mixture is neutralized with a base to extract 3,4-methylenedioxy-mandelic acid in an organic solvent layer, and separating the organic solvent layer and an aqueous layer, and
(C) an oxidation reaction step wherein the aqueous layer is removed and the organic solvent layer is concentrated, and then, nitric acid is added to a concentrate, and the 3,4-methylenedioxymandelic acid and nitric acid are reacted to form piperonal.
In the present invention, as mentioned above, the following three steps are continuously carried out without taking out 3,4-methylenedioxymandelic acid which is an intermediate as a crystal in the course of the reaction.
(A) Addition reaction step in which 1,2-methylenedioxy-benzene and glyoxylic acid are reacted in the presence of a strong acid to form 3,4-methylenedioxymandelic acid.
(B) Extraction step in which an organic solvent is then added to the reaction mixture, followed by neutralization with a base, whereby extracting 3,4-methylenedioxymandelic acid in an organic solvent layer, to separate the organic solvent layer and an aqueous layer.
(C) Oxidation reaction step in which the aqueous layer is then removed, and after concentrating the organic solvent layer, nitric acid is added to the concentrate whereby 3,4-methylenedioxymandelic acid and nitric acid are reacted to form piperonal.
In the following, the above-mentioned three steps are successively explained.
(A) Addition Reaction Step
The addition reaction step of the present invention is a step of forming 3,4-methylenedioxymandelic acid by reacting 1,2-methylenedioxybenzene and glyoxylic acid in the presence of a strong acid.
As a strong acid to be used in the addition reaction step of the present invention, there may be preferably mentioned inorganic acids such as sulfuric acid, phosphoric acid, etc., more preferably sulfuric acid. Also, as these strong acids, 70% by weight or more of an aqueous solution is preferably used. An amount thereof to be used is preferably 0.50 to 3.00 mole, more preferably 1.00 to 2.50 mole based on 1 mole of 1,2-methylenedioxybenzene.
As the glyoxylic acid to be used in the addition reaction step of the present invention, either of a solid (monohydrate) or 40% by weight or more of an aqueous solution may be used. An amount thereof to be used is preferably 0.8 to 2.0 mole, more preferably 1.0 to 1.5 mole based on 1 mole of 1,2-methylenedioxybenzene.
The addition reaction step of the present invention is carried out in the presence or absence of a reaction solvent. As a solvent to be used, it is not particularly limited so long as it is stable under acidic conditions and does not inhibit the reaction, and there may be mentioned, for example, organic acids such as formic acid, acetic acid, propionic acid, n-butyric acid, i-butyric acid, n-valeric acid, trifluoroacetic acid, dichloroacetic acid, etc.; ethers such as diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, etc.; ketones such as acetone, 2-butanone, 3-pentanone, 2-pentanone, 4-methyl-2-pentanone, cyclopentanone, cyclohexanone, etc.; carboxylic acid esters such as ethyl formate, isopropyl formate, butyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, methyl propionate, ethyl propionate, isopropyl propionate, butyl propionate, etc.; amides such as N,N-dimethylformamide, 1-methyl-2-pyrrolidone, etc.; ureas such as 1,3-dimethyl-2-imidazolidone, etc.; carbonic esters such as dimethyl carbonate, diethyl carbonate, etc., and preferably ketones are used.
An amount of the above-mentioned reaction solvent to be used is preferably 100 to 2000 ml, more preferably 100 to 1000 ml based on 1 kg of the 1,2-methylenedioxybenzene. These reaction solvents may be used singly or in admixture of two or more.
The addition reaction step of the present invention is carried out, for example, by adding glyoxylic acid and a strong acid to a mixed solution of 1,2-methylenedioxy-benzene and a reaction solvent in an atmosphere of an inert gas such as nitrogen or argon, etc., or the like. The reaction temperature at that time is preferably xe2x88x9220 to 10xc2x0 C., more preferably xe2x88x9210 to 5xc2x0 C. Also, the reaction is usually carried out under normal pressure, but may be carried out under pressure or a reduced pressure, if necessary.
(B) Extraction Step
The extraction step of the present invention is a step in which, after the addition reaction step, an organic solvent is added to the reaction mixture, and then, neutralizing with a base, thereby 3,4-methylenedioxymandelic acid is extracted with the organic solvent layer, to separate the organic solvent layer and an aqueous layer.
As the organic solvent to be used in the extraction step of the present invention, there may be mentioned ketones such as acetone, 2-butanone, 3-pentanone, 2-pentanone, 4-methyl-2-pentanone, cyclopentanone, cyclohexanone, etc.; organic acid esters such as ethyl formate, isopropyl formate, butyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, methyl propionate, ethyl propionate, isopropyl propionate, butyl propionate, etc.; ethers such as diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, etc., preferably ketones are used.
An amount of the above-mentioned organic solvent to be used is not particularly limited so long as it is an acid in the extraction step, and for example, it is used in an amount of 1 to 10 kg based on 1 kg of 3,4-methylenedioxymandelic acid.
As the base to be used in the extraction step of the present invention, an aqueous alkali metal hydroxide solution (for example, an aqueous sodium hydroxide solution or an aqueous potassium hydroxide solution, etc.) or an aqueous ammonia is suitably used. As a concentration of the aqueous alkali metal hydroxide solution, 10 to 48% by weight is preferred, and as a concentration of the aqueous ammonia, 5 to 28% by weight is preferred.
An amount of the above-mentioned base to be used is an amount necessary for neutralizing the strong acid used in the addition reaction step, and is preferably 2 equivalents based on 1 equivalent of sulfuric acid.
The extraction step of the present invention is carried out, for example, by a method in which an organic solvent is added to the reaction mixture obtained in the addition reaction step, then the reaction mixture is neutralized with a base preferably at xe2x88x9220 to 50xc2x0 C., more preferably at xe2x88x9220 to 10xc2x0 C., thereby extracting 3,4-methyl-enedioxymandelic acid with the organic solvent layer, to separate the organic solvent layer and an aqueous layer, or the like. Incidentally, the extraction operation is carried out preferably at 20 to 100xc2x0 C., more preferably at 40 to 80xc2x0 C. Also, the extraction operation is usually carried out under normal pressure, but may be carried out under pressure or reduced pressure, if necessary.
(C) Oxidation Reaction Step
The oxidation reaction step of the present invention is a step in which, after the extraction step, the aqueous layer is removed and the organic solvent layer is concentrated, and then, nitric acid is added to the concentrate whereby reacting 3,4-methylenedioxymandelic acid and nitric acid to form piperonal.
The nitric acid to be used in the oxidation step of the present invention is preferably a 5 to 70% by weight aqueous solution. An amount thereof is preferably 0.5 to 1.0 mole, more preferably 0.55 to 0.8 mole based on 1 mole of 1,2-methylenedioxybenzene to be charged.
In the oxidation reaction step of the present invention, depending on necessity, after concentrating an organic solvent layer, a reaction solvent is newly added to react 3,4-methylenedioxymandelic acid and nitric acid.
As the above-mentioned reaction solvent, there may be mentioned, for example, aromatic hydrocarbons such as toluene, xylene, ethylbenzene, etc.; halogenated aromatic hydrocarbons such as chlorobenzene, etc.; ketones such as acetone, 2-butanone, 3-pentanone, 2-pentanone, 4-methyl-2-pentanone, cyclopentanone, and cyclohexanone; halogenated aliphatic hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, dibromoethane, etc.; ethers such as diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, etc., preferably aromatic hydrocarbons and ketones are used.
An amount of the above-mentioned reaction solvent is preferably 1000 to 8000 ml, more preferably 1500 to 5000 ml based on 1 kg of the 1,2-methylenedioxybenzene. These reaction solvents may be used alone or in admixture of two or more kinds.
Also, if necessary, water may be newly added. An amount thereof to be used is not particularly limited so long as it can control a nitric acid concentration in the reaction mixture preferably 5 to 50% by weight, more preferably 5 to 20% by weight.
The oxidation reaction step of the present invention is carried out, for example, by a method in which an aqueous layer is removed from a separated solution obtained in the extraction step, and after concentrating the organic solvent layer, nitric acid is added in an atmosphere of an inert gas such as nitrogen or argon, etc., and the like. The reaction temperature at that time is preferably 5 to 100xc2x0 C., more preferably 15 to 80xc2x0 C. Also, the reaction is generally carried out at normal pressure, and if necessary, it may be carried out under pressure or under reduced pressure.
The resulting final product (piperonal) is extracted, for example, by a suitable solvent after neutralization by addition of a suitable amount of a base, and separated and purified by a conventional means such as column chromatography, distillation, recrystallization and the like.
Incidentally, the organic solvent removed in the concentration operation in the oxidation reaction step or a reaction solvent removed at the time of obtaining a final product may be recovered and used again in the above-mentioned addition reaction step, extraction step or oxidation reaction step.